The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Publications in this area include WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4xe2x80x2 position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans.
Thus the invention provides a compound of formula (1) which is an agonist at the adenosine A1 receptor 
wherein
X represents O or CH2; 
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 alkylO(CH2)n where n is 0-6, C3-7 cycloalkyl, C1-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, C1-6 alkenyl or C1-6 alkynyl group optionally substituted by one or more halogens.
Y and Z represent O, N, CH, N(C1-6 alkyl)
W represents CH, O, N, S, N(C1-6 alkyl)
xe2x80x83and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
xe2x80x83with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-16 straight chain or branched alkyl group.
R1 represents hydrogen or a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring 
xe2x80x83wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-13alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)m-NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
xe2x80x83and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.
Preferably the compound is of formula (Ia) 
wherein
X represents O or CH2; 
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 straight or branched alkyl optionally substituted by one or more halogens, C3-7 cycloalkyl, C1-6 hydroxyalkyl or halogen.
Y and Z represent O, N, CH
W represents CH, O, N, S
xe2x80x83and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
xe2x80x83with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring 
xe2x80x83wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, -(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
xe2x80x83and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
The invention further provides pharmaceutical compositions of formula (I) or (Ia) together with a pharmaceutically acceptable diluent or carrier.
It will be appreciated that certain compounds embraced by formula (I) are novel per se. A particular group of compounds may be defined by formula (Ib). Therefore, the invention further provides compounds of formula (Ib) which are agonists at the adenosine A1 receptor 
wherein
X represents O or CH2. 
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6alkylO(CH2)n where n is 0-6, C3-7 cycloalkyl, C1-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, C1-6 alkenyl or C1-6 alkynyl group optionally substituted by one or more halogens.
Y and Z represent O, N, CH, N(C1-6 alkyl)
W represents CH, O, N, S, N(C1-6 alkyl)
xe2x80x83and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
xe2x80x83with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents hydrogen or a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-2 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring 
xe2x80x83wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
xe2x80x83with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3, C1-3alkoxy and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Preferably, the compound is of formula (Ic): 
wherein X represents O or CH2; 
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 straight or branched alkyl optionally substituted by one or more halogens, C3-7 cycloalkyl, C1-6 hydroxyalkyl or halogen.
Y and Z represent O, N, CH
W represents CH, O, N, S
xe2x80x83and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
xe2x80x83with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring 
xe2x80x83wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
xe2x80x83with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3, C1-3alkoxy
xe2x80x83and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Conveniently the adenosine A1 agonists of the general formula (I) above exhibit greater activity at the adenosine A1 receptor than the other adenosine receptor subtypes, particularly A3. More particularly the compounds exhibit little or no agonist activity at the the A3 receptor.
It will be appreciated that wherein R1 and/or R2 in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula (I) above.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R1 and R2 include methyl, ethyl, n-propyl, 1-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl.
As used herein, the term xe2x80x9calkylenexe2x80x9d means a straight or branched chain alkylene group containing 1-6 carbon atoms, e.g. methylene.
As used herein, the term xe2x80x9cC2-6alkenylxe2x80x9d means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable C2-6alkenyl group.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
By aliphatic heterocyclic group defined for R1 is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may optionally be substituted as defined hereinabove.
The term heterocyclic aromatic group defined for R1 refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may optionally be substituted as defined hereinabove.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. A particularly suitable pharmaceutically acceptable salt of the compounds of formula (I) is the hydrochloride salt. Other acids such as oxalic, while not, in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may be, for example, hydrates.
Examples of W, Y and Z containing heterocyclic groups include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles and thiadiazoles.
Preferred W, Y and Z containing heterocyclic groups are isoxazoles, and 1,2,4 - and 1,3,4-oxadiazoles.
R2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.
Conveniently, R1 may represent (alk)n-C3-6 cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted. Preferably n is zero. More preferably, the cycloalkyl group is unsubstituted or monosubstituted with OH and more preferably the cycloalkyl ring has 5 carbon members. Most preferably, the cycloalkyl group is hydroxycyclopentyl.
Alternatively R1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of xe2x80x94CO2xe2x80x94(C1-4)alkyl.
Conveniently, the aliphatic heterocyclic group is unsubstituted or when the substituent is xe2x80x94CO2(C1-4)alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.
Preferably the heterocyclic ring is 6 membered and more preferably contains only one O, N or S heteroatom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N.
Alternatively, R1 may represent a straight or branched alkyl of 1-6 carbon atoms optionally with at least one S(xe2x95x90O)n and where S(xe2x95x90O)n is present, optionally substituted with N at a position adjacent to the S(xe2x95x90O)n group; where there is an S(xe2x95x90O)n in the chain, substitution with N at a position adjacent to the S(xe2x95x90O)n group is preferred; where there is an S(xe2x95x90O)n in the chain, preferably n is 1 or 2, more preferably n is 2. The alkyl group conveniently may be unsubstituted or substituted by at least one OH group.
Alternatively R1 may represent a phenyl group which is substituted by one or two substituents selected from OH, alkyl, particularly C1-4 alkyl and halogen. Preferably the phenyl is disubstituted in the 2,4 positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro.
Preferably R4 and R5 represent hydrogen.
It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned above.
Particular novel compounds include compounds of Examples 1-207 herein below.
Preferred compounds include:
(2S,3 S,4 R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
4-{9-[5S-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester;
(2S,3S,4R,5R)-2-(5-Isopropyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
4-{9-[5S-(5-Cyclopropyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester;
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluoro-phenylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(5-Ethyl-oxazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxy-cyclopent-(S)-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxy-cyclopent-(S)-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4 R,5R)-2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(tetrahydro-pyran4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-tert-Butyl-isoxazol-5-yl)-5-[6-(tetrahydro-pyran4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
ethyl 4-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2S,3S,4 R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-{6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-[6-(isobutylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(cyclopropylamino)-9H-purin-9-yl]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
2-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)-N-methylethanesulfonamide;
(2R,3R,4S,5S)-2-[6-(3,4-difluoroanilino)-9H-purin-9-yl]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3S,4 R,5 R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5R)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4 R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-{6-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol;
2-[(9-{(2R,3 R,4S,5S)-5-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide;
2-[(9-{(2R,3R,4S,5S)-5-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-(3-methylphenyl)ethanesulfonamide;
2-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(5-methyl-1,3-oxazol-2-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)-N-methylethanesulfonamide;
(2R,3R,4S,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]-5-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(5-ethyl-1,3,4-oxadiazol-2-yl)-5-[6-(isopropylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(6-{[(1 S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-{2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol formate (1:2);
(2R,3R,4S,5S)-2-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-5-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-tetrahydro-furan-3,4-diol diformate;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol;
ethyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2R,3S,4R,5R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3S,4R,5R)-2-(5-isopropyl-4H-1,2,4-triazol-3-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(5-methyl-1,3-oxazol-2-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-methylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-propylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
ethyl 4-({2-chloro-9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(2-chloro-6-{[2-(ethylsulfonyl)ethyl]amino}-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(3-ethyl isoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazo-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol;
ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate;
(2S,3S,4R,5R)-2-[3-(hydroxymethyl)isoxazol-5-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5R)-2-{2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3,4-diol formate;
(2S,3S,4R,5R)-2-(3-bromoisoxazol-5-yl)-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(methylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(propylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(isopropylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-isopropylethanesulfonamide
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-pyridin-3-ylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(4-hydroxybutyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
(2R,3R,4S,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol
ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-cyclopropylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-{6-[(1-butyrylpiperidin-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol isopropyl 4-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(2,2,2-trifluoroacetyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
methyl 4-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
2-[(2-chloro-9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
ethyl 4-[(2-chloro-9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[2-methoxy-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
ethyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-2-methoxy-9H-purin-6-yl}amino)piperidine-1-carboxylate
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[2-(ethylsulfonyl)ethyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-2-methoxy-9H-purin-9-yl]-5-(3-ethyl isoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(2-fluoroanilino)-2-methoxy-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-2-methoxy-9H-purin-9-yl]-5-(3 ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-[6-(cyclopropylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol.
Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease plasma free fatty acid concentrations. The compounds may thus be used in the treatment of hyperlipidaemias. Furthermore, as a consequence of their anti-lipolytic activity, the compounds have the ability to lower elevated blood glucose, insulin and ketone body levels and therefore may be of value in the therapy of diabetes. Since anti-lipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also show anti-atherosclerotic activity. The anti-lipolytic activity of compounds of the invention has been demonstrated by their ability to lower the concentration of non-esterified fatty acids (NEFA) in starved rats dosed orally according to the method described by P. Strong et al. In Clinical Science (1993), 84, 663-669.
In addition to their anti-lipolytic effect, the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction. The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina.
Furthermore, the compounds of the invention are useful as cardioprotective agents, having applicability in the treatment of ischaemic heart disease. As used herein the term xe2x80x9cischaemic heart diseasexe2x80x9d includes damage associated with both myocardial ischaemia and reperfusion, for example, associated with coronary artery bypass grafting (CABG), percutaneous translumenal coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention additionally are useful for treating ischaemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders arising as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and stroke.
The compounds may also inhibit renin release and thus be of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents (e.g. as hypnotics, sedatives, analgesics and/or anti-convulsants particularly finding use in the treatment of epilepsy).
In addition, the compounds of the invention may find use in the treatment of sleep apnoea.
The compound of formula (I) and pharmaceutically acceptable acid addition salts thereof are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically of a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compound of formula (I) and its pharmaceutically acceptable acid addition salts may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis (RA) and osteoarthritis (OA), neuropathic pain (e.g. post herpetic neuralgia (PHN), trigeminal neuralgia, neuropathies associated with diabetes and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of formula (I) may also be used in the treatment or prevention of pain associated with migraine, tension headache and cluster headaches and pain associated with Functional Bowel Disorders (e.g. Irritable Bowel Syndrome), non cardiac chest pain and non ulcer dyspepsia.
Additionally, when topically administered, the compounds of the present invention exhibit analgesic and anti-inflammatory activity and are therefore useful in a number of chronic inflammatory pain conditions such as OA, RA and neuropathic conditions such as fibomyalgia and PHN.
Accordingly, the invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or whereby the therapy involves the treatment of ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from a CNS disorder, sleep apnoea or pain.
In a further aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain, which method comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a human or animal suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ishaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain.
In respect of the above mentioned ischaemic treatment, it has been found that according to a particularly unexpected aspect of the present invention, not only does administration of a compound of formula (I) prior to ischaemia provide protection against myocardial infarction, but protection is also afforded if the compound of formula (I) is administered after the ischaemic event and before reperfusion. This means that the methods of the present invention are applicable not only where ischaemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischaemia, for example in heart attack and unstable angina.
It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.
The pharmaceutical composition comprises, as active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from a CNS disorder, sleep apnoea or pain.
There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and/or excipient.
Compositions according to the invention may be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions may be adapted for sustained release.
For topical administration, the pharmaceutical composition may be given in the form of a transdermal patch.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents (e.g. mannitol) as appropriate.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
A proposed dose of the compounds of the invention for administration to man (of approximately 70 kg body weight) is 1 mg to 2 g, preferably 1 mg to 100 mg, of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration.
In a yet further aspect the invention also provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease (PVD) or stroke, or which patient is suffering from a CNS disorder, sleep apnoea or pain.
The compounds of formula (I) and physiologically acceptable salts or solvates thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups R1, R2 and R3 are as defined for compounds of formula (I) unless otherwise stated.
According to a first general process A, a compound of formula (I) may be prepared by reacting a compound of formula (II) 
wherein L represents a leaving group such as a halogen atom (e.g. chlorine), or a linker group capable of binding to a solid phase polymeric support (e.g. a polystyrene resin) and for example may be xe2x80x94SO2C1-4alkylene and P1 and P2 represent hydrogen, C1-6 straight chain or branched alkyl or a suitable protecting group (e.g. acetyl or a protecting group wherein P1 and P2 together form an alkylidine group) with a compound of formula R1NH2 or a salt thereof under basic conditions. The 4xe2x80x2-heterocycle group substituent may be protected if required, for example, see route Bb and V described hereinbelow.
Compounds of formula (II) may be used to produce compounds of formula (I) directly by reaction with the group R1NH2 either in the absence or presence of a solvent such as an alcohol (e.g. a lower alkanol such as isopropanol, t-butanol or 3-pentanol), an ether (e.g. tetrahydrofuran or dioxan), a substituted amide (e.g. dimethylformamide), a halogenated hydrocarbon (e.g. chloroform), an aromatic hydrocarbon (e.g. toluene), dimethyl sulfoxide (DMSO) or acetonitrile, preferably at an elevated temperature (e.g. up to the reflux temperature of the solvent), in the presence of a suitable acid scavanger, for example, inorganic bases such as sodium, cesium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine, optionally in the presence of a palladium catalyst (e.g. palladium acetate) and phosphine ligand (e.g. R-(+)-2,2xe2x80x2-bis(diphenylphosphino)-1-1xe2x80x2binaphthyl).
Optionally, where at least one of Y, Z and W is N, alkylation may be carried out on a N atom at Y, Z or W at any appropriate stage in the synthesis, for example, see Route X described hereinbelow.
The above reactions may be preceded or followed where appropriate by in situ removal of the P1 and P2 protecting groups. For example when P1 and P2 represent acetyl, this may be effected with an amine such as ammonia or tert-butylamine in a solvent such as methanol or when P1 and P2 represent an alkylidine by acid hydrolysis, e.g. with trifluoroacetic acid (TFA). Interconversion of P1 and P2 protecting groups may occur at any stage in the preparation of the compounds of formula (II), for example when P1 and P2 represent acetyl, compounds of formula (II) may be prepared from compounds wherein P1 and P2 together represent an alkylidine protecting group by acid catalysed removal of the alkylidine protecting group, e.g. with hydrogen chloride in methanol followed by in situ acylation, for example with acetic anhydride in the presence of a base such as pyridine, in a solvent such as dichloromethane.
Otherwise, interconversion of P1 and P2 protecting groups may occur at any stage during the preparation of compounds of formula (II).
It will be apparent to persons skilled in the art that in the preparation of compounds of formula (II) or (I) the 4xe2x80x2-heterocycle may be formed at any stage. For example, heterocycles may be prepared from carboxylic acid or acetylene starting materials before the addition of the purine ring (see Schemes 1, 1 a and 2) or heterocycles may be formed after the addition of the purine ring (see Schemes 3, 4 and 5 and Route W).
Compounds of formula (II) where Xxe2x95x90O may be prepared by reacting compounds of formula (III) 
wherein P3 represents a suitable protecting group, for example acetyl, or a substituent such as C1-3 alkyl, and P1, P2 and R3 are as defined above, with compounds of formula (IV) 
wherein L and R2 are as defined above.
The reaction is conveniently carried out in a suitable solvent, such as acetonitrile in the presence of a silylating agent such as trimethylsilyl trifluoromethane sulfonate and a base such as diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively the compound of formula (IV) may first be silylated with a suitable silylating agent e.g. hexamethyldisilazane followed by reaction of the silylated intermediate with a compound of formula (III) and a suitable Lewis acid, e.g. trimethylsilyl trifluoromethanesulfonate in a suitable solvent such as acetonitrile.
Compounds of formula (IV) are either known in the art or may be prepared from known compounds using methods analogous to those used to prepare the known compounds of formula (IV).
As described above, the compounds of formula (III) may be prepared from alternative protected compounds by replacement of the alternate P1 and P2 protecting groups with other P1 and P2 groups. These represent an exchanging of one protecting group for another and will be apparent to those skilled in the art. Compounds of formula (III) may be made for example by the following syntheses:
Compounds of formula (III) may be prepared, for example when the heterocycle defined by W, Y and Z hereinabove represents an isoxazole (optionally substituted) by the following reaction schemes. 
General conditions for Stages 1-4 will be known to persons skilled in the art. It will also be appreciated that the reagents and conditions set out in Scheme 1 are example conditions and alternative reagents and conditions for achieving the same chemical transformation may be known to persons skilled in the art. P4 and P5 together represent alkylidine protecting group(s). P6 represents C1-4 alkyl. R3 is as previously defined.
Although scheme 1 shows the preparation of compounds of formula (III) where the heterocycle moiety is an isoxazole it would be apparent to a person skilled in the art that other standard methods could be employed to produce compounds of formula (III) with other heterocycles from carboxylic acid starting materials, such a compound of formula (IIIa), for example, see route Q as described hereinbelow.
An alternative method for synthesis of compounds of formula (III) is shown in Scheme 1 a. 
General conditions for Stages 1-5 in Scheme 1 a will be known to persons skilled in the art. R3, P1, P5 and P6 are as previously defined.
Scheme 2 represents a method of preparing compounds of formula (III) when Yxe2x95x90N, Zxe2x95x90NH, Wxe2x95x90CH and R3xe2x95x90H or tautomers thereof. P1, P2 and P6 are as previously defined. 
A further process (B) comprises converting a compound of formula (I) into a different compound of formula (I) by modifying the R1, R2 and/or R3 groups therein.
All compounds of formulae (III) are novel intermediates and form a further aspect of the present invention.
Compounds of the formula R1NH2 are either known compounds or may be prepared from known compounds using conventional procedures.
Specific optical isomers of a compound of formula (I) may be obtained by conventional methods for examples by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or where appropriate by separation of a mixture of isomers of a compound of formula (I) by conventional means e.g by fractional crystallisation or chromatography.
According to a third process (C), compounds of formula (I) may be prepared from compounds of formula (V) or (VI): 
where R1, R2,X, L, P1 and P2 represent groups as previously defined.
Also compounds of formula (VI) may be prepared from compounds of formula (V) by analogous methods to those described in process (A) above.
Synthesis of the compounds of formulae (I) from the corresponding acids of formulae (V) and (VI) will be apparent to a skilled person using conventional synthetic techniques.
As an example, when Wxe2x95x90O, Yxe2x95x90N and Zxe2x95x90N in formula I above thus defining a 1,3,4 oxadiazole, the synthesis is according to reaction scheme 3. J represents a leaving group L as previously defined, or a NHR1 group. R2, X, P1 and P2 are as previously defined. 
Compounds of formula (I) where Zxe2x95x90O, Yxe2x95x90N and Wxe2x95x90N (thus defining a 1,2,4-oxadiazole) may be prepared from compounds of formula (V) or (VI) by a first process involving activation of the carboxyl group on the compound of formula (V) or (VI) followed by reaction with an amidoxime of formula HOxe2x80x94Nxe2x95x90C(R3)NH2 in a solvent such as tetrahydrofuran or chloroform, in the presence of a base such as pyridine or di-isopropylethylamine, followed by cyclisation at a temperature of 20xc2x0 C.-150xc2x0 C. in a solvent such as toluene, tetrahydrofuran (THF) or chloroform (see scheme 4). Methods of carboxyl activation include reaction with an acid chloride, such as pivaloyl chloride, or an acid anhydride in the presence of a base such as a tertiary amine, for example di-isopropylethylamine, or with thionyl chloride in dimethylformamide (DMF). Activating agents used in peptide chemistry such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, may also be used. Hydroxyl protecting groups may be removed under conditions known to those practising in the art. For example, the acetonide group may be removed by treatment with an acid (at a temperature of 0xc2x0 C.-150xc2x0 C.) such as trifluoroacetic acid suitably at 0-20xc2x0 C. or acetic acid suitably at 50-150xc2x0 C.
In scheme 4 R2, R3, X, J, P1 and P2 and are as defined above. 
Alternatively, a compound of formula (II) may be prepared from a compound of formula (VII), for example, see route U as described hereinbelow. It would be apparent to persons skilled in the art that analagous methods to route U could be used to prepare compounds of formula (I) with other 4xe2x80x2-heterocycles, for example, see route M as described hereinbelow. 
According to an general process D, a compound of formula (I) may be prepared from a compound of formula (V), as shown in Scheme 5, followed by removal of the P1 and P2 protecting groups as described previously in process A. It will be apparent to persons skilled in the art that analagous methods to that shown in Scheme 5 could be used to prepare compounds of formula (I) with other 4xe2x80x2-heterocycles using alternative heterocycle syntheses. In Scheme 5, R1, R3, J, P1 and P2 are as previously defined. 
The invention is further illustrated by the following non limiting intermediates and Examples.
Full experimental details are given below for routes A-Z, Bb and Cc; data for remaining examples prepared by analogous routes are given in Table 1.
Standard HPLC conditions are as follows:
Standard Automated Preparative HPLC Column, Conditions and Eluent
Automated preparative high performance liquid chromatography (autoprep. HPLC) was carried out using a Supelco ABZ+5 m 100 mmxc3x9722 mm i.d. column eluted with a mixture of solvents consisting of 1) 0.1% formic acid in water and ii) 0.05% formic acid in acetonitrile, the eluent being expressed as the percentage of ii) in the solvent mixture, at a flow rate of 4 ml per minute. Unless otherwise stated the eluent was used as a gradient of 0-95% (ii) over 18.5 minutes.
LC/MS System
Four alternative Liquid Chromatography Mass Spectroscopy (LC/MS) systems were used:
System A:
This system used an ABZ+PLUS, 3.3 cmxc3x974.6 mm i.d. column, eluting with solvents: Axe2x80x940.1% v/v formic acid+0.077% w/v ammonium acetate in water; and Bxe2x80x9495:5 acetonitrile:water+0.05% v/v formic acid, at a flow rate of 1 ml per minute. The following gradient protocol was used: 100% A for 0.7 mins; A+B mixtures, gradient profile 0-100% B over 3.5 mins; hold at 100% B for 3.5 mins; return to 100% A over 0.3 mins.
System B:
This system used an ABZ+PLUS, 3.3 cmxc3x972.0 mm i.d. column, eluting with solvents: Axe2x80x940.1% v/v formic acid+0.077% w/v ammonium acetate in water, and Bxe2x80x9495:5 acetonitrile:water+0.05% v/v formic acid, at a flow rate of 0.8 ml per minute. The following gradient protocol was used: A+B mixtures, gradient profile 0-100% B over 3.5 mins; hold at 100% B for 1.5 mins; return to 100% A over 0.5 mins.
System C:
This system used an ABZ+PLUS, 3.3 cmxc3x974.6 mm i.d. column, eluting with solvents: Axe2x80x940.1% v/v formic acid+0.077%w/v ammonium acetate in water; and Bxe2x80x9495% acetonitrile:water+0.05% v/v formic acid, at a flow rate of 3 ml per minute. The following gradient protocol was used: 100% A for 0.7 mins; A+B mixtures, gradient profile 0-100% B over 3.7 mins; hold at 100% B for 0.9 mins; return to 100% A over 0.2 mins.
System D:
This system used an ABZ+PLUS, 3.3 cmxc3x974.6 mm i.d. column, eluting with solvents: Axe2x80x940.1% v/v formic acid in water; and Bxe2x80x9495% acetonitrile:water+0.07% v/v formic acid, at a flow rate of 1.5 ml per minute. The following gradient protocol was used: 100% A for 0.2 mins; A+B mixtures, gradient profile 0-100% B over 3.3 mins; hold at 100% B for 1 min; return to 100% A over 0.2 mins.
All LC/MS systems used a micromass xe2x80x98platformxe2x80x99 spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u.
Flash chromatography was carried out either on Merck silica gel (Merck 9385), or on pre-packed silica gel cartridges (Biotage).
All temperatures were in xc2x0 C.
Experimental Details for Route (A)
Intermediate 1
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid Nxe2x80x2-(2,2-dimethyl-propionyl)-hydrazide
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (2.5 g) suspended in 1,2-dimethoxymethane (100 ml) was treated with 2,2-dimethyl-propionic acid hydrazide (1.1 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the mixture heated under reflux for 16 h. The mixture was poured into aqueous citric acid (250 ml) and extracted with ethyl acetate; the organic layers were washed with citric acid and brine, dried (MgSO4) and evaporated in vacuo to give the crude product. Purification by flash chromatography on silica gel (Biotage cartridge), eluting with ethyl acetate:cyclohexane 65:35, gave the title compound as a white solid (1.92 g).
LC/MS (System B): Rt 2.49 min
Mass spectrum m/z 439 [MH+].
Intermediate 2
9-[6S-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-2,2-dimethyl-tetrahydro-(3aR,6aS)-furo[3,4-d][1,3]dioxol-4R-yl]-6-chloro-9H-purine
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid Nxe2x80x2-(2,2-dimethyl-propionyl)-hydrazide (1.5 g) was dissolved in thionyl chloride (15 ml) and the solution irradiated in a microwave oven at 150W power for 7 min. The excess thionyl chloride was evaporated in vacuo to give the crude product which was dissolved in dry acetonitrile (6 ml) and heated under reflux for 3 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel, eluting with ethyl acetate:cyclohexane 35:65-40:60, to give the title compound as a white solid (0.645 g).
LC/MS (System B): Rt 2.86 min
Mass spectrum m/z 421 [MH+].
Intermediate 3
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol
9-[6S-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-2,2-dimethyl-tetrahydro-(3aR,6aS)-furo[3,4-d][1,3]dioxol-4R-yl]-6-chloro-9H-purine (0.64 g) was treated with 10:1 trifluoroacetic acid:water (9 ml) at 0xc2x0 C. for 5 h, and the mixture was allowed to stand in the refrigerator (2xc2x0) overnight. The mixture was evaporated in vacuo to low volume (ca. 1 ml), poured into ice cold aqueous sodium bicarbonate, and extracted with ethyl acetate (3xc3x9750 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give the crude product (371 mg).
LC/MS (System B) Rt 2.42 min
Mass spectrum m/z 381 [MH+].